Rationale: There is uncertainty on the use of using triple therapy (inhaled corticosteroids/long-acting β-agonist/long-acting muscarinic antagonist) inhaler therapy for patients with chronic obstructive pulmonary disease (COPD), who complain of dyspnea and/or exercise intolerance.

Objectives: We conducted a systematic review and meta-analyses to estimate the safety and efficacy of using triple therapy compared with long-acting β-agonist/long-acting muscarinic antagonist dual therapy or monotherapy with a single long-acting bronchodilator in patients with stable COPD who complained of dyspnea and/or exercise intolerance.

Methods: A search of MEDLINE, Embase, and the Cochrane Library databases was conducted for randomized controlled trials pertaining to the clinical question. A systematic approach was used to screen, abstract, and critically appraise the studies. The grading of recommendations assessment, development, and evaluation method was applied to rate the certainty/quality of the evidence.

Results: Eleven studies were eligible for inclusion (n = 14,145 patients). Pairwise random-effects meta-analysis revealed an increase in risk of pneumonia (relative risk, 1.48; 95% confidence interval [95% CI], 1.23–1.79; P < 0.001) and decreased risk of acute exacerbations of COPD (AECOPDs) (relative risk, 0.75; 95% CI, 0.68–0.82; P < 0.001) with triple therapy compared with treatment with dual and monotherapy long-acting bronchodilator therapy. No significant difference in dyspnea scores (standardized mean difference, 0.09; 95% CI, −0.02 to 0.19; P = 0.09) or risk of hospitalization (rate ratio, 0.78; 95% CI, 0.58–1.06; P = 0.11) was noted. When subgroup analysis based on inhaler class was performed, no significant difference was noted between the groups in any of the critical outcomes studied. For patients with a history of one or more AECOPDs in the past year, triple therapy resulted in 230 fewer AECOPDs and 16 more cases of pneumonia per 1,000 patients.

Conclusions: In patients with COPD who complain of dyspnea and/or exercise intolerance, triple therapy is not superior to maintenance long-acting bronchodilator therapy, except in patients with a history of one or more exacerbations in the past year, in whom the benefits of reduction in AECOPD outweigh the increased risk of pneumonia.